Experimental pulmonary metastases resulting from intravenous injection of murine fibrosarcoma cells were studied by electron microscopy. Sequential sections of pulmonary tissue were fixed at various times after tumor cell injection. Cells arrested in pulmonary capillaries within minutes of injection and appeared to attach to the vascular endothelium by surface pseudopodia. Shortly thereafter, platelets aggregated around the impacted tumor cells. No fibrin deposition was identified in such platelet thrombi. Platelets disaggregated within 18 hours, leaving tumor cells adherent to vascular endothelium by short pseudopods. Tumor cells then penetrated between endothelial cells to enter the perivascular connective tissue and give rise to metastatic cell deposits by mitosis. Ultrastructural examination of experimental pulmonary metastases produced in mice by injection of melanoma cells resulted in similar observations of cell behavior as was seen in the fibrosarcoma system. The melanoma cells, however, remained free in the circulation longer, aggregated platelets less, and penetrated vascular walls more quickly than the fibrosarcoma cells. Comparison of the ultrastructural events in melanoma metastasis formation between normal mice and mice anticoagulated with warfarin showed no significant differences, except a relative delay in vascular penetration by arrested tumor cells in the anticoagulated animals. Mice treated with cyproheptidine were demonstrated to have depressed platelet counts and depressed platelet function in vitro. The incidence of spontaneous pulmonary metastases was compared between tumor-bearing cyproheptidine-treated and tumor-bearing controls. For a fibrosarcoma which aggregated platelets in vitro, a significant decrease in pulmonary metastases was observed in the treated group. For a melanoma which had no platelet-aggregating activity, no difference in incidence of metastases was observed between treated and control animals.